This invention relates to chewing gums and in particular to their use in the delivery of active ingredients, including liquid solutions of active ingredients, thermolabile active ingredients in solid or liquid form and homeopathic medicines.
The use of chewing gum as a drug delivery vehicle is well known and under extensive investigation by many researchers (see, for example, xe2x80x9cChewing gum as a drug delivery systemxe2x80x9d, Margrethe Romer Rassing, Advanced Drug Delivery Reviews, 13, 89-121 (1994)). Apart from the fact that chewing gum offers a convenient and easily used vehicle for active ingredient administration, it presents additional features of pharmacological importance including the fact that absorption of active ingredients through the oral mucosa avoids hepatic first pass metabolism, and may therefore offer an opportunity to reduce therapeutic dose requirements.
The primary disadvantage of chewing gum is a difficulty in regulating the total dose administered. In many cases it is impossible to formulate gum such that the total dose contained is released and made available for absorption.
While buccal absorption of active ingredients avoids liver metabolism, the act of chewing produces saliva which necessitates swallowing and there is no way of regulating the amount of active ingredient which is swallowed and the amount absorbed through the buccal mucosa. Furthermore, active ingredients which are poorly water-soluble are not easily absorbed when present in chewing gum in solid form.
Another problem is thermal stability: the industry standard method of formulating any chewing gum involves a hot melt process in which the temperature of the gum base (to which active ingredients, flavours and excipients are added as a dry powder) may be of the order of 80xc2x0 C. Thermolabile active ingredients are denatured by the high processing temperatures and thus cannot be formulated for delivery using the industry standard process technology.
A solution to this problem has been proposed which avoids the high temperatures of the hot melt process. By freezing the gum it can be comminuted by grinding, and then an active ingredient can be added in powdered form. The mixture of powdered active ingredient and frozen gum particles can be compressed together and thawed. Processes of this type are disclosed in: U.S. Pat. No. 4,000,321, U.S. Pat. No. 4,161,544 and U.S. Pat. No. 4,737,366.
WO 96/03111 discloses details of comminution of gum to a powdered form followed by blending with liquid ingredients, before compression to the form of tablets which are then subsequently dried by hot air.
Despite the disadvantages, there are many suitable active ingredient candidates some of which are already available in the market in chewing gum form. These active ingredients include nicotine, anti-microbials for local oral infection, fluoride gums for prevention of dental caries, vitamins and some functional foods. The common feature of all commercial products is that they are intended for local oral application of the active ingredient and, like ointments or other conventional topical medicaments, the total dose administered is not critical to the therapeutic value.
The delivery of liquids presents its own problems, particularly where aqueous solutions are involved. A major problem in entrapping water in chewing gums is that water (and liquids such as water/ethanol solutions which are often used as a base for homeopathic dilutions) are not compatible with conventional chewing gum processing. There is no point in enclosing a discrete volume of water en masse in a gum envelope because the volume bursts out in the first bite. So a problem exists in finding some way of dispersing the aqueous solution in the gum such that it is released slowly over a period of about twenty minutes, without subjecting the active ingredient to some incompatible conditions such as extreme heat, shearing, electromagnetic forces or chemical manipulation.
If a liquid must be encapsulated, other methods can be used, such as using a resin which holds a polar liquid therein by charge attraction (such as the nicotine gums marketed by Kabi Pharmacia as xe2x80x9cNicorettexe2x80x9d); or the liquid can be encapsulated in liposomes (also referred to as nanospheres/microspheres depending on size) and these particles can be entrapped in a gum in much the same way as with a powder. The use of xe2x80x9cmicro-spongesxe2x80x9d, containing encapsulated liquids is disclosed in U.S. Pat. No. 5,154,927. Using these methods the total volume of liquid which can be encapsulated is very small, being approximately 0.1 ml for a standard sized piece of gum.
The present invention aims to provide gums in which significantly more liquid (e.g. up to 1.0 ml or more) can be formulated in each piece of gum.
Therefore, it is an object of this invention to provide a chewing gum product giving improved sustained release of active ingredients and one which is particularly suitable for thermolabile biological ingredients and other medicaments some of which may be required to be in liquid solution.
The invention provides a method of manufacturing a chewing gum comprising the steps of:
a) entrapping a liquid within a mass of gum;
b) cooling the gum by an amount sufficient to freeze the entrapped liquid and thereby form entrapped frozen liquid crystals within the gum; and
c) regulating the temperature of the gum so as to manipulate the size and/or morphology of the frozen liquid crystals, and thereby manipulate the internal structure of the gum to provide a gum having spaces therein of a plate-like or sheet-like shape.
It has been found that by controlling the size and/or morphology of the frozen crystals inside the gum matrix, it is possible to obtain good control of the internal spaces inside the gum. The distribution of an active ingredient in the liquid is thus controllable, and this has a significant impact on the release characteristics of the gum.
Preferably, a step a) comprises comminuting the gum to a particulate form and adding the liquid thereto.
The liquid can thus act as a binder for the particulate gum. The liquid may be an active ingredient in itself, or it may contain an active ingredient (or a flavouring) in solution, suspension or homeopathic dilution. Alternatively, a simple liquid such as water may be added simply in order to use the frozen crystals of water to control the internal structure of the gum. If the water is subsequently removed, one is left with xe2x80x9cblanksxe2x80x9d which are adapted to absorb a liquid in the internal spaces vacated by the water.
Preferably, the comminution of the gum is achieved by a process selected from jet milling, homogenisation in a suspending liquid, and cryogenic milling.
The operation of a jet mill is well known to those skilled in the art. In jet milling, particle size reduction occurs from collisions between particles driven at high speeds by cold nitrogen gas. As a starting material, commercially available gum base is supplied in particulate form of a size suitable for feeding into a jet mill. Particles whose size is sufficiently reduced exit the mill chamber automatically.
In homogenisation in a suspending liquid, pieces of gum are suspended in a liquid such as a saturated aqueous salt solution. A commercially available homogeniser is used to reduce the gum particles to an extremely fine suspension. The operation occurs at a suitably low temperature to allow the gum to be effectively chopped. As an alternative to a salt solution, any liquid having a low enough freezing point may be used.
In cryogenic milling, the gum is frozen and ground to a suitable size by any known method of comminuting a brittle mass.
Alternatively, step a) may comprise melting the gum, adding a liquid thereto, and forming an emulsion of the liquid in the melted gum.
This method is less preferred as it is unsuitable for substances which are denatured at high temperatures. However, it may be suitable for robust ingredients, or for simple liquids such as water when water is added on its own.
Preferably, step b) comprises blast freezing the gum to a solid state.
Blast freezing is rapid freezing obtained by creating the maximum temperature differential between the unfrozen mass and a freezing surface, thereby achieving the maximum heat flow rate from the freezing mass. When the liquid contains an active ingredient in solution, blast freezing tends to cause the water and solute molecules to take up a much smaller crystal structure relative to those that would be present if freezing was effected at slower rates. The initially smaller crystal structures allow room for more crystal growth when the temperature is varied during annealing (as described below). This in turn allows the water/gum matrix to be better compacted during ice annealing.
Suitably, the gum is frozen to a temperature which is more than 10xc2x0 C. below the freezing point of said liquid.
Preferably, step c) comprises regulating the temperature of the gum while maintaining the liquid in frozen form.
In particularly preferred embodiments, step c) comprises bringing the gum to a temperature at which the crystals undergo annealing.
During annealing, the frozen crystals grow and bond with one another. In so doing, they generate pressure at the interface with the gum, compressing the pieces of gum together (when the gum has been formed by adhering comminuted gum particles together).
The structure of the crystals generated by annealing determines the distribution of the liquid within the gum. In particular when the liquid comprises water, the ice crystals tend to anneal into sheet-like or plate-like structures which subsequently provide a sustained release of an ingredient contained in the spaces formed during annealing.
Preferably, the annealing temperature to which the gum is brought in step c) is sufficiently warm to cause the gum to exhibit plasticity without allowing the liquid to melt.
At such temperatures, the plasticity of the gum facilitates the crystals annealing together and enables the structure of the gum matrix to be manipulated, which in turn influences the release characteristics of the gum during chewing.
Further, preferably, the temperature to which the gum is brought in step c) is within 5xc2x0 C. of the melting point of the frozen liquid.
Suitably, the gum is maintained at an annealing temperature for not less than 2 hours.
The process of crystal growth during annealing is relatively slow, and the morphology of the crystals is thus determined both by the annealing temperature and the duration of the annealing step.
In certain embodiments, step c) comprises thawing the liquid and re-freezing the liquid at least once, more preferably at least three times.
This can be referred to as xe2x80x9cfreeze-thaw texturisingxe2x80x9d the gum. The individual particles of gum are compressed together with a relatively large force arising from the advancing ice front as the liquid freezes. Repetition of the freeze-thaw cycle gives rise to a gum having a good consistency, and indeed allows the consistency to be accurately controlled.
In preferred embodiments, the method further comprises the step of:
d) removing the liquid from the gum after step c).
In particular, unless it is important for the liquid to be actually present in the finished gum, the preferred finished product will generally be a dry gum. In particular, removal of the liquid will leave behind any suspended or dissolved ingredients, thereby providing a gum in which these ingredients are incorporated within spaces whose size and shape has been determined by the aforementioned temperature control.
If no ingredient is entrapped, then the removal of liquid provides xe2x80x9cblanksxe2x80x9d of gum which are adapted to absorb a liquid into the spaces vacated during removal of the original liquid. Even if no other liquid is absorbed by the blanks, the texture of the gum will be different from conventional gums, since the gum will be interlaced with internal spaces. Thus, a gum is provided which may be advantageous in and of itself, without any emphasis on the delivery characteristics or any entrapped ingredients. From the point of view of manufacturers, such gums utilise fewer ingredients for a given size piece of gum (i.e. a given volume), because much of the internal volume of the gum is filled with air (or another gaseous substance if desired).
Preferably, step d) comprises subjecting the gum to vacuum-assisted freeze drying.
Freeze drying enables the liquid to be extracted from the gum matrix while leaving the spaces originally occupied by the frozen liquid substantially intact. In general, the removal of liquid by freeze drying opens channels from the internal frozen crystals to the surface of the gum. These channels can be re-sealed by coating the gum or by light compression of the surface of the gum.
In preferred embodiments, the liquid comprises a solvent in which a solute has been dissolved, and the solvent is removed to leave the solute entrapped in the gum.
In alternative embodiments, the method further comprises the step of:
dxe2x80x2) sealing the gum with the liquid intact either before or after thawing the gum.
This is most suitable when the gum is to be used to deliver a liquid per se, such as a liquid active ingredient or a homeopathic dilution. The volume of liquid entrapped using this method is substantially greater than in prior art methods of entrapping a liquid in a gum.
According to the invention it is possible to get the powdered gum to absorb about 40% of its own weight without feeling wet. The loaded gum can be pressed into a tablet shape and then dipped into molten gum to form a seal. The sustained release characteristics of the gum can be enhances, by freezing, thawing and re-freezing the loaded gum. The end result is a piece of gum consisting of a gum envelope, enclosing a compressed powdered gum matrix, with a water-based solution in the inter-particulate spaces. As an alternative to dipping the loaded pieces of gum in a molten coating, it is possible to seal the porous surface of the compressed gum granules after the liquid active ingredient has been absorbed. For example one can use brief contact with a hot metal surface to seal the gum pieces.
In a further modification of the method according to the invention the gum is mechanically compressed during steps b) and c).
External mechanical compression adds to the internal pressure generated by ice annealing, and further adds to the integrity of the finished pieces of gum.
Suitably, the liquid added in step a) contains a thermolabile substance.
As indicated above, the invention is particularly suitable for such substances as it allows a gum to be prepared while avoiding the use of any elevated temperatures. Thermolabile substances are denatured at unsuitable temperatures, including many biologically important substances, particularly proteins such as enzymes, antibodies and hormones.
Suitably, the liquid added in step a) comprises a homeopathic preparation.
Homeopathic preparations are made by successive dilutions of an active ingredient, to a point (in many cases) where one would expect no molecules of active ingredient to remain in an average sample. Such medicines are widely used, and are generally administered as a liquid or as a lactose pillule which has absorbed the liquid. The present invention provides for the first time a method of incorporating an active ingredient in aqueous form in a finished sustained release gum without subjecting the liquid to elevated temperatures.
A particularly advantageous application of chewing gum prepared according to the invention is in the area of oral medicine. In oral healthcare there are many clinical indications which would benefit from sustained delivery of therapeutic products from chewing gum, examples of these would include xerostomia (dry mouth syndrome), oral thrush, dental caries, gingivitis, periodontitis and mouth ulcers.
There are many conventional medicines available in different formulations designed to treat these conditions. The application of chewing gum preparations is more advantageous when long-term prophylactic use is desired. Many conventional medicines are unsuitable for prophylactic applications due to long-term side effects. Many biological preparations, which would provide long-term prophylaxis, are heat sensitive and are not easily incorporated into chewing gum using the industry standard process.
Suitably, the liquid added in step a) contains one or more purified constituents of egg.
For example, Irish Patent Specification No. 65218 describes a method of developing hyper-immune egg yolk antibodies against the organisms causing oral thrush, and the contents of this patent specification are incorporated herein by reference. Thus, egg immunoglobulin may be used to replicate the constituents of saliva. It is equally feasible to develop antibodies against any oral pathogen, and to combine these with other constituents of egg such as lysosyme to effectively mimic the protective effect of human saliva which will have wide ranging prophylactic applications in oral medicine.
Accordingly, in preferred embodiments the liquid added in step a) contains one or more constituents having biological activity characteristic of human saliva.
Patients suffering from xerostomia are not only disadvantaged by the discomfort and difficulty of having a dry mouth. Because of the immune activity of saliva, such patients are also highly susceptible to oral infection, which makes the incorporation of immune constituents in a gum particularly advantageous.
Suitably, the liquid added in step a) contains a herbal extract. In preferred embodiments, the herbal extract is Vaccinium myrtilis or Melissa officianalis. 
Vaccinium myrtilis is known to have vasoprotective properties in oral applications (see Morazzoni and Bombardelli, Fitoterapia; LXVII, No. 1, 1996). Similarly the extract of Melissa officinalis is known to have therapeutic properties in viral ulceration of the mouth (see Wolbling and Leonhardt, Phytomedicine, 1, 25-31(1994)).
In another aspect, the invention provides a chewing gum comprising a gum matrix having spaces within the gum matrix, characterised in that the size and/or morphology of the spaces is determined during the manufacture of the gum by a change in the size and/or morphology of crystals of an entrapped frozen liquid present during manufacture, and in that the spaces have a plate-like or sheet-like shape due to the formation and growth of ice crystals during manufacture.
Such gums provide for a controlled and sustained release of active ingredient, and as indicated above, they enable a significantly higher dose load to be included (up to 1 ml liquid per 3.1 g piece of gum, as opposed to approximately 0.1 ml in the prior art).
As previously described, in certain embodiments the entrapped frozen liquid present during manufacture has been removed from the finished product.
This provides a gum having a xe2x80x9choneycombxe2x80x9d of internal spaces which give the gum a lighter consistency and an improved mouthfeel.
Preferably, the spaces in the finished product contain a residual material originally dissolved or suspended in said liquid.
In alternative embodiments, the spaces in the finished product contain said liquid in thawed form.
Preferably, the spaces are of an average size greater than the average maximum size of individual liquid volumes which can be incorporated in a gum matrix, due to the use of an annealing step which encourages crystal growth between adjacent crystal structures.
Thus, while only relatively small crystals may be formed during the initial freezing of the gum, annealing enables larger volumes to form by adjacent crystals annealing together.
Preferably, the entrapped frozen liquid present during manufacture is a liquid of a type hereinbefore defined.
A further method of entrapping the liquid in the gum is by creating an emulsion of aqueous drug in a gel of gum base in hexane or cyclohexane or similar suitable solvent. The morphology of the dispersed drug can be fixed by rapid freezing of the emulsion and evaporation of the solvent to deposit gum on the frozen droplets of drug. The resulting particles can then be compressed together to obtain a mass of gum having an entrapped liquid, and this mass can then be subjected to freeze-thaw texturising as described herein. Similarly, particles of liquid-containing gum can be obtained by vacuum-assisted cryogenic spheronisation of drug in a polymer, as described in WO-A-95/22036, the contents of which are incorporated herein by reference.